cGMP-dependent protein kinase and iron metabolism

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Iron is a vital metal ion required for the proper function of essential proteins and a critical element in many cellular functions. Iron is resorbed mostly by the duodenal enterocytes, is then transported in the blood by transferrin, and stored bound to ferritin in liver, bone marrow, erythroblasts, and skeletal muscle. Hemoglobin contains about half of the bodys iron. Iron absorption is tightly regulated in the intestine and controlled by the hepatic factor hepcidin. Hepcidin inhibits the iron exporter ferroportin present in macrophages and at the basolateral side of the enterocyte. The transcription of hepcidin is stimulated by proinflammatory cytokines such as IL-6, and inhibited by hypoxia, erythropoietin, and lack of iron. We have generated mouse lines that express cGKIa or cGKIb under the SM22a promoter in smooth muscle cells (rescue mice). Analysis of these mice and conventional knock-out mice revealed that cGKI-/- or cGKI rescue mice develop a bleeding ulcus duodeni, anemia and a severe deficit of iron. The decreased iron availability resulted in a decreased hemoglobin concentration and erythrocyte content. The same animals had significantly elevated plasma levels of reticulocytes and erythropoietin supporting the notion that the cGKI modified mice had an iron-deficiency anemia. We were unable to rescue the phenotype in the rescue animals by i.m. injection of iron. cGKI-/- mice show enhanced apoptosis of erythrocytes in the spleen. However, premature apoptosis of the erythrocytes in the spleen would not explain the very low iron content of the spleen, because erythrocytes are degraded in macrophages, which store the iron released during hemoglobin degradation and provide it for the resynthesis of hemoglobin. In agreement with these results, untreated cGKI rescue mice had elevated mRNA expression of the transferrin receptor and of the divalent metal ion transporter in the spleen suggesting the iron deficiency is sensed by the reticuloendothelial cells of the spleen. As expected, the iron storage protein ferritin is reduced to nearly zero level in the spleen of untreated cGKI mouse lines and does increase only slightly with the injection of iron. These results are indicative of an iron absorption/storage deficit of the spleen macrophages.Preliminary data show that cGKI-/- and the cGKI rescue mice have anemia caused by a severe iron deficit in the spleen. Oral or i.m. supplementation of iron has not restored the spleen iron deficit nor the anemia. Very preliminary data even suggest that treatment of the animals with PPIs that prolongs dramatically the live span of a subset of the cGKI-/- mice does not change the anemia. Goal of this project is to understand at which level cGKI affects the iron metabolism, because so far no interaction between iron metabolism and cGKI has been reported.